TIPE2 protein negatively mediates restoration of myeloid dendritic cells in patients with chronic hepatitis B

doi:10.21203/rs.3.rs-3411762/v1

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TIPE2 protein negatively mediates restoration of myeloid dendritic cells in patients with chronic hepatitis B

https://doi.org/10.21203/rs.3.rs-3411762/v1

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Background

Hepatitis B virus (HBV) causes persistence in a subgroup of patients and impaired myeloid dendritic cells (mDCs) functions have been observed in these patients, and the effect could be remedied by treatment with interferon-α (IFN-α)-based antiviral therapies. However, the biological functions of mDCs in HBV infection remains largely unexplored.

Methods

TIPE2 expression in mDCs was analyzed by qRT-PCR, western blot and flow cytometry. The release of cytokines was assessed using enzyme-linked immunosorbent assay (ELISA). Downregulation of TIPE2 expression was constructed via siRNA.

Results

Our results showed that TIPE2 was significantly increased in mDCs isolated from chronically HBV-infected subjects compared with healthy subjects or patients achieving antiviral treatment of sustained virological responses (SVR). Interestingly, IFN-α treatment could decrease the expression of TIPE2 in mDCs from HBV patients than that untreated patients, SVR patients, or healthy subjects. Moreover, TIPE2 expression in mDCs was decreased in healthy subjects but not HBV patients after stimulating with poly I:C, while the difference could be abrogated by the treatment with IFN-α in vitro. In addition, TIPE2 expression by poly I:C activated mDCs, with or without IFN-α treatment, negatively correlated with the expression of CD86 and CCR7, and the secretion of interleukin-12 (IL-12), but positively associated with the production of IL-10. Finally, downregulation expression of TIPE2 could increase the production of IL-12 and decrease IL-10 secretion in mDCs of chronically HBV-infected individuals.

Conclusions

Our study suggested that TIPE2 was a crucial factor in negatively mediating innate immune responses during chronic viral infection.

TIPE2

Hepatitis B virus

myeloid dendritic cells

IFN-α

Hepatitis B virus (HBV) have resulted in approximately 400 million people developing liver cirrhosis or hepatocellular carcinoma, and eradicating the HBV is regarded as a major public health challenge [1, 2]. In recent years, IFN-α therapy has become one of therapeutic methods and restores HBV-specific CD8 T-cell responses by sequential low-dose IL-2 treatment in non-responder patients [3]. There has been reported that inadequate innate immunity responses to virus is the major characteristic of chronic HBV infection [4, 5]. Immune cells, including T cells and natural killer (NK) cells, play a pivotal role in controlling virus infection [6]. Dendritic cells (DCs) are the essential cells for initiating and regulating innate and adaptive immune after responding to viral infection. Plasmacytoid dendritic cells (pDCs) and myeloid DCs (mDCs) are the main subsets of DCs [7]. Viral nucleic acids, single stranded RNA, and unmethylated DNA motifs could be recognized by pDCs via Toll- like receptors (TLRs) [8]. Previous study has demonstrated that the functions of pDCs was altered in patients with chronic HBV infection [9]. The mDCs are derived from a myeloid bone marrow precursor and the most potent antigen-presenting cells. Dysfunction of mDCs may be the primary cause of impaired T-cell responses in HCV-infected individuals. In addition, the capacity of mDCs to induce a mixed lymphocyte response is reduced in HCV-infected individuals [10–12]. However, whether mDCs are able to affect chronic HBV infection has not been reported.

Indeed, mDCs isolated from chronically HCV-infected patients show a reduced impaired maturation and decreased interleukin-12 (IL-12) production [13]. Intriguingly, recent studies indicate that treatment with interferon-α (IFN-α)/ ribavirin (RBV) restores the function of mDCs in HCV patients, a finding that correlates with higher antiviral T-cell responses [14]. However, the mechanisms underlying mDC dysfunction in chronic HBV infection and functional restoration by IFN-α-based therapy remain largely unknown.

The tumor necrosis factor (TNF)-α-induced protein 8-like 2 (TIPE2), one of new protein of the TNFAIP8 (a.k.a TIPE) family and play an essential role in maintaining immune homeostasis by negatively regulating T cell receptor and Toll-like receptor (TLR) signaling [15, 16]. TIPE2 protein was highly expressed in inflamed but not normal nervous tissue and regarded as an inflammation-related gene [17]. Deletion of TIPE2 could result in multiorgan inflammation in mice and its abnormal expression in humans is associated with hepatocellular carcinoma, diabetic nephropathy, stroke, and atherosclerosis [18]. Previous studies demonstrated that the TIPE2 mRNA expression were downregulated in peripheral blood mononuclear cells (PBMC) of chronic hepatitis B patients, which indicated the negative correlation between TIPE2 and HBV infection [19]. Additionally, a recent study shows that TIPE2 can suppress the autophagic activity of DCs by inhibiting the TAK1/JNK signaling pathway and further negatively regulate the immune function of DCs in the development of septic complications [20]. Similarly, DCs undergone TIPE2 knockdown were found to promote the maturation of DCs, T-cell proliferation as well as differentiation [19]. These data indicate that TIPE2 plays a critical role in controlling DC function.

In this study, we found that TIPE2 expression was up-regulated in mDCs isolated from patients with chronic hepatitis B and could be corrected by the treatment with IFN-α. To illustrate the effect of TIPE2 on mDCs, we detected TIPE2 expression and its function in human mDCs stimulated with or without PolyI:C or IFN-α. Our data indicated that TIPE2 was upregulated and negatively associated with IL-12 production in both unstimulated poly I:C stimulated mDCs from HBV patients. Interestingly, TIPE2 expression was significantly decreased after treatment of IFN-α in mDCs, and restored the HBV-mediated suppression of IL-12. In addition, silencing TIPE2 expression increased the production of IL-12 in mDCs of chronically HBV-infected individuals.

Clinical specimens

HBV-infected patients and healthy subjects were enrolled in this study. According to different clinical immune types of HBV infection, the subjects were divided into three groups: treatment naïve patients (n = 20), IFN-α/RBV antiviral therapy (n = 20), patients achieved SVR (n = 20), healthy subjects (n = 20) were act as control. Testing of the HBV viral load was performed by the Department of Infectious Diseases, Henan Provincial People's Hospital, Zhengzhou University People's Hospital. Written informed consent was obtained from all subjects. This study was approved by the institutional review boards of Henan Provincial People's Hospital, Zhengzhou University People's Hospital.

Isolation and culture of mDCs

Myeloid DCs were isolated from PBMCs, which were isolated from whole blood by density gradient centrifugation using the BDCA-1⁺ Dendritic Cell Isolation Kit (Miltenyi Biotech, Auburn, CA) according to the manufacturer’s instructions. The mDCs were cultured seeded in a 96-well plate at 2🞨10⁵ cells/mL in 0.2 mL of RPMI-1640 (Gibco) containing 5% fetal bovine serum, 100 µg/mL penicillin-streptomycin and 2mM L-glutamine (Gibco). The mDCs were stimulated in culture medium supplemented 50 µg/mL poly I:C (Invivogen, San Diego, CA) with or without IFN-α (1000U/ml; Roche, Shanghai, China).

Flow Cytometry Analysis

The expression of TIPE2 in mDCs were stained using DyLight488-conjugatedanti-TIPE2 antibody after incubating in the darkness for 20 min, and then analyzed on a FACS AriaII flow cytometer (BD, Piscataway, NJ). Finally, CELL QUEST software was utilized to quantify the data.

RNA isolation and qRT-PCR

The total RNA of mDCs was isolated by RNeasy Minikit (Qiagen, Hilden, Germany) and ReverTra Ace qPCR RT Kit (TaKaRa, Dalian, China) was used to obtain cDNA according to the manufacturer’s protocol. qRT-PCR was performed in ABI 7500 StepOnePlus system (Applied Biosystems, CA, USA). All primers were shown: TIPE2 forward primer: 5′-TTTGCTACGACACTCGGAAC-3′, TIPE2 reverse primer: 5′-TTCTGAGGATGTTGCTGAGG-3′, GAPDH forward primer: GTCTCCTCTGACTTCAACA GCG, GAPDH reverse primer: ACCACCCTGTTGCTGTAGCCAA.

Western blot (WB)

The mDCs were lysed in RIPA buffer (Beyotime, Shanghai, China), and separated by 10% SDS-PAGE for 2h. The proteins were transferred onto a nitrocellulose membrane, blocked with 5% bovine serum albumin (BSA) for 1h and then incubated with diluted primary antibodies to TIPE2 (1:2,000, ab169616) and GAPDH (1:2,000, ab371685) overnight at 4 ℃. The membrane was incubated with second antibodies for 35 min at room temperature. The band density was measured with a computer-assisted image analysis system (Adobe Systems, San Jose, CA, USA).

Enzyme-linked immunosorbent assay

The levels of IL-12p70 and IL-10 secreted into the culture supernatant by mDCs were measured by using enzyme-linked immunosorbent assay (ELISA) kits (Pierce Endogen, Rockford, IL) according to the manufacturer’s instructions.

TIPE2 siRNA silencing

The mDCs were incubated with 10 µM TIPE2 siRNA duplex or control siRNA in 200mL siRNA Blank Medium in a six-well plate according to the manufacturer’s instructions. After 6 h, the Blank Medium was replaced with normal growth medium. The transfected cells were then incubated for 18-72h, and then the cells were collected to detect the expression of TIPE2, IL-12p70 and IL-10 as described previously.

Statistical analyses

GraphPad 7.0 was used for data analysis. The data were shown as mean ± standard deviation (SD). All samples were analyzed by t-test or one-way ANOVA with a significance level of P < 0.05.

Higher expression of TIPE2 is shown in mDCs from HBV-infected patients than healthy subjects and down-regulated after treatment with IFN-α

Our previous study has found that the expression level of TIPE2 mRNA was increased in myeloid DCs (mDCs) of patients with chronic hepatitis B compared with that of healthy subjects (data not shown). To further explore the role of TIPE2 in mDCs, we isolated mDCs from PBMCs of four groups of subjects by sorting with anti-BDCA-1magneticbeads. The data demonstrated that both mRNA and protein expression of TIPE2 were upregulated in chronically HBV-infected individuals (treatment-naïve patients), while TIPE2 expression was significantly lower in patients undergoing the treatment of IFN-α-based antiviral compared with treatment-naïve patients and healthy subjects, suggesting that TIPE2 expression is down-regulated by IFN-α-based antiviral therapy. In addition, TIPE2 expression in patients achieving SVR was lower than HBV treatment-naïve patients, but higher than patients undergoing IFN-α therapy, and had no significant difference with healthy subjects (Fig. 1A-C). These results indicated that TIPE2 was up-regulated in mDCs from HBV infection patients but down-regulated by IFN-α therapy.

TIPE2 mRNA expression in mDCs is down-regulated after treatment of IFN-α

There has been reported that mDCs play a vital role in regulating the development of chronic HBV patients, while the mechanisms of mDCs remain to be further explored [21]. Given the effect of TIPE2 in immunological function of mDCs [22], we hypothesized that TIPE2 might be a key factor of mediating mDCs in HBV infection. Hence, mDCs were isolated from HBV-infected individuals and healthy subjects, and stimulated with poly I:C for 12h. As shown in Fig. 2A, the TIPE2 mRNA expression in mDCs from healthy subjects was significantly reduced upon stimulation with 50 µg/mL poly I:C. However, there was no significance of TIPE2 mRNA expression in mDCs isolated from HBV patients after stimulation of poly I:C. In addition, though TIPE2 mRNA expression in mDCs isolated from both treatment-naïve patients and healthy subjects was significantly decreased upon stimulation with either 1000U/mL IFN-α or IFN-α/poly I:C (Fig. 2B, C), TIPE2 mRNA expression in stimulation of IFN-α/poly I:C was down-regulated more than that IFN-α alone. In a word, these data suggested that TIPE2 expression in mDCs might be dysregulated by chronic HBV infection and IFN-α synergistically sensitized mDCs to TLR stimulation.

TIPE2 expression is negatively related toCD86 and CCR7 expressions in mDCs by IFN-α treatment

CD86 and CCR7 are the key molecules of DCs for the antigen presentation, immune activation and homing to secondary lymphoid organs [23–25]. To further certify the relationship between TIPE2 expression and mDC function, we examined the expression of TIPE2, HLA-DR, CD86 and CCR7 in mDCs stimulated with poly I:C, IFN-α, or IFN-a/poly I:C by WB. Our data showed that the expression of TIPE2 protein was consistent with mRNA expression Fig. 3A. Similarly, both CD86 and CCR7 expression were consistently higher in mDCs isolated from healthy subjects than those from HBV patients after stimulation with poly I:C (Fig. 3B, C). Our data suggested that the change of mDCs phenotype induced by IFN-α from HBV patients may be associated with TIPE2 expression.

IL-12 production is improved, whereas IL-10 is inhibited, in mDCs by IFN-α treatment in vitro

IL-12 and IL-10 produced by mDCs play an important role in mediating inflammation [26, 27]. Hence, we detected the production of these cytokines by mDCs after treated with poly I:C, IFN-α, or IFN-α/poly I:C. The data showed that the secretion of IL-12 by mDCs from HBV patients was much less than those from healthy subjects, while IL-12 expression was increased after treatment with IFN-α or IFN-α/poly I:C (Fig. 4A). On the contrary, though IL-10 production by mDCs from HBV patients was lower, their levels were still significantly higher compared with healthy subjects (Fig. 4B). Next, we explored the relation of TIPE2 expression and mDCs phenotype or cytokine production. We found that TIPE2 expression was negatively correlate with the expression of CD86 (Fig. 5A), CCR7 (Fig. 5B) and IL-12 secretion (Fig. 5C). In contrast, TIPE2 expression was positively correlate with IL-10 production (Fig. 5D).

The secretion of IL-12 and IL-10 in mDCs from treatment-naïve patients are mediated by TIPE2

To investigate whether TIPE2 participated in the production of IL-12 and IL-10 in HBV-infection, TIPE2 expression in mDCs isolated from treatment-naïve patients were downregulated by siRNA transfection. The data demonstrated that TIPE2 mRNA expression and protein expression were significantly silenced in mDCs transfected with TIPE2 siRNA compared with control siRNA (Fig. 6A, B). Consistent with the previous results, HBV-mediated inhibition of IL-12 expression by mDCs was corrected (Fig. 6C) and the production of IL-10 was decreased (Fig. 6D). All in all, these data indicated that TIPE2 expression was upregulated by HBV, while negatively related to IL-12 expression in mDCs.

TIPE2, also known as TNFAIP8L2, is originally identified as an inflammation-related gene and a newly identified immunomodulator to negatively regulating immune homeostasis [19]. At present, the study has identified that TIPE2 plays an important role in taming HBV-induced hepatic inflammation [28], but the mechanism of TIPE2 in mDCs during chronic HBV infection or in response to IFN-α-based antiviral therapy remains unclear.

Dendritic cells (DCs) play a significant role in mediating innate and adaptive immune, including pDCs and mDCs. Dysfunction of mDCs might was observed in HCV-infected individuals and the treatment with IFN-α/RBV restores the immune function of mDCs.¹⁴ In this study, we found that higher expression of TIPE2 in mDCs isolated from chronically infected HBV patients compared with healthy subjects and TIPE2 expression was downregulated upon stimulation by IFN-α. The mRNA expression of TIPE2 in mDCs isolated from both treatment-naïve patients and healthy subjects was markedly downregulated after treatment with IFN-α, while more significantly decrease was observed after addition of the IFN-α/poly I:C.

mDCs upregulate the expression of related markers, such as MHC class I and II molecules, and co-stimulatory molecules to mediate antigen presentation and immune activation after binding and taking up antigens [29]. Besides, mature mDCs increase their expression of CCR7 to migrate towards chemokines constitutively expressed in the secondary lymphoid organs [30]. Immature mDCs express CCR1, CCR2 and CCR5; the ligands for these receptors are produced at sites of inflammation and act as chemoattractant for DCs [31–33]. In addition, the production of IL-12 and IL-10 by mDCs are the vital elements in balancing the inflammation responses. We found that TIPE2 expression was negatively associated with the expression of the co-stimulatory molecule CD86 and chemokine receptor CCR7, as well as the secretion of IL-12, but positively correlated with the production of IL-10 in poly I:C activated mDCs, with or without IFN-α treatment. Moreover, downregulation of TIPE2 could increase the production of IL-12 and decreased IL-10 secretion in mDCs isolated from treatment-naïve patients.

In conclusion, our study demonstrated that TIPE2 expression was upregulated, which closely correlated with mDC dysfunction in HBV-infected patients, and can be rescued by the IFN-α treatment. This presents a novel and crucial role for TIPE2 as a negative regulator of DC function in innate immune responses to HBV infection. These results may help to clarify the molecular mechanisms underlying the immune response to chronic HBV infection, and identify new targets for immune therapy of HBV infection.

Acknowledgements

Not applicable.

Author contributions

LM, YHK, and YK conceptualized and designed the study. LM, YHK, JFW, XMQ, and XW supported project implementation, data collection, and data source. LM, YHK, and YHK supported data management, statistical analysis, and manuscript drafting. All authors read and approved the final manuscript.

Funding

This work was funded by Henan Provincial Health Commission joint project (LHGJ20210034).

Availability of data and materials

Data and materials are available upon request from Dr. Yi Kang (Email: [email protected]).

Competing interests

The authors declare that they have no competing interests.

Ethics approval and consent to participate

This study was approved by the institutional review boards of Henan Provincial People's Hospital, Zhengzhou University People's Hospital.

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No competing interests reported.

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Version 1

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You are reading this latest preprint version

TIPE2 protein negatively mediates restoration of myeloid dendritic cells in patients with chronic hepatitis B

Status:

Version 1

Abstract

Background

Methods

Results

Conclusions

Figures

Background

Materials and methods

Clinical specimens

Isolation and culture of mDCs

Flow Cytometry Analysis

RNA isolation and qRT-PCR

Western blot (WB)

Enzyme-linked immunosorbent assay

TIPE2 siRNA silencing

Statistical analyses

Result

TIPE2 mRNA expression in mDCs is down-regulated after treatment of IFN-α

TIPE2 expression is negatively related toCD86 and CCR7 expressions in mDCs by IFN-α treatment

The secretion of IL-12 and IL-10 in mDCs from treatment-naïve patients are mediated by TIPE2

Discussion

Conclusion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1